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Potential Roles and Limitations of Biomarkers in Alzheimer’s Disease

Potential Roles and Limitations of Biomarkers in Alzheimer’s Disease. Richard Mayeux, MD, MSc Columbia University. Biomarkers and Disease. Natural history Risk prediction Phenotype definition Clinical and biological heterogeneity Diagnostic or screening tests Response to treatment

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Potential Roles and Limitations of Biomarkers in Alzheimer’s Disease

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  1. Potential Roles and Limitations of Biomarkers in Alzheimer’s Disease Richard Mayeux, MD, MSc Columbia University

  2. Biomarkers and Disease • Natural history • Risk prediction • Phenotype definition • Clinical and biological heterogeneity • Diagnostic or screening tests • Response to treatment • Prognosis

  3. Use of Biomarkers in Epidemiology and Clinical Medicine Traditional Exposure Disease Biological or Molecular Epidemiology Markers of ExposureBiomarkers of Disease Exposure dose biological effect Altered clinical prognosis structure/ diagnosis function

  4. Disease Pathway risk factors screening & diagnosis prognosis induction latency disease detection pathogenesis Alzheimer Disease biomarkers etiology

  5. Steps to Develop Biomarker selection of type: risk factor vs. disease surrogate validity of relation to disease field methods dose-response modifiers sensitivity & specificity population variation

  6. Risk or Predictors

  7. Temporal Relationship Past Present Future Case-control Biomarker Disease “odds of exposure” Cohort Study Biomarker Disease “risk of disease”

  8. Exposure-Biomarker-Disease Association 3. E1 IM1 D E2 IM2 1. IM1 D • IM1 D • IM2 4. E1 IM1 D E2 IM2 5. E U D IM1 One or two intermediate biomarkers sufficient to cause disease Exposures mediated via intermediate biomarker(s) or exposure is related to an unknown event associated with biomarker

  9. Select candidates relevant to disease pathway Identify and quantitate the association between the maker and the disease For intermediate markers consider attributable proportion Strategy to Validate Biomarkers of Risk Disease Biomarker yes no Present A B Absent C D Sensitivity (S) = A/A+C RR= [A/(A+B)]/[C/(C+D)] Attributable proportion = S(1-1/RR)

  10. Relation Between Predictive Value and Frequency of Biological Marker sensitivity specificity Predictive value frequency

  11. Screening & Diagnosis

  12. Diagnostic & Screening Tests Sensitivity = a/a+c (true positives/patients) Specificity = d/b+d (true negatives/healthy) *PPV = a/a+b (true positives/trait present) *NPV = d/c+d (true negatives/trait absent) *Prior probability = a+c/N (patients/total population)

  13. Relation Between Prior Probability and Predictive Values for a Test (90/90) predictive values PPV NPV prevalence or prior probability

  14. Evaluation of Diagnostic Tests • Receiver operating characteristic ( ROC) • Estimates probabilities of decision outcomes • Provides an index of the accuracy decision criterion • A measure of detection and misclassification • Efficacy = practical (or “added”) value

  15. Utility of APOE Genotype in Diagnosis of Alzheimer’s Disease sensitivity false positive rate

  16. Requirements for Screening Tests • Test must be quick, easy and inexpensive • Test must be safe, acceptable to persons screened and physicians or health care workers screening • Sensitivity, specificity and predictive values must be known and acceptable to medical community • Adequate follow-up for screened positives with and without disease

  17. Prognosis • Same rules apply: • Sensitivity and specificity • Validity of outcome and exclusion of confounders • Relation between stage of disease and marker

  18. Biomarkers: What Is Needed? Study design, implementation, coordination & analysis Administrative support Biostatistics Exposure Assessment Effects Assessment Field work Interviewers Specimen collectors Field lab Data management Laboratory Specimen banker Collaborating investigators, institutions, etc Registry and database Laboratory Manager Technicians Specimen banker Registry

  19. Source Donor problem Collection equipment Technician Transport/handling Storage Receipt and control errors (e.g.Transcription) Solutions Procedures manual Document storage Monitor specimens for degredation Maintain records Quality control program Measurement Errors

  20. Sources Specimen unrelated to exposure or disease Differential availability related to exposure or disease Specimen acquisition, storage, analysis or procedures related to exposure or disease Solutions High response rate rate Document procedures to monitor selection bias Keep track of specimen usage Aliquot & use small portions Use reviewed by objective panel Bias

  21. Sources Failure to identify potential intermediate factors or related biomarkers (e.g. BMI, use of laboratory kits) Failure to adjust for confounders in the analyses Solutions Use data on confounders in designing study Collect relevant data on acquisitions, transport, storage and laboratory personnel changes Discuss confounders with biostatistician Confounding

  22. Biomarkers • Advantages • objective • precision • reliable/valid • less biased • disease mechanism • homogeneity of risk or disease status • Disadvantages • timing • expensive • storage • laboratory errors • normal range • statistics • ethical responsibility

  23. It’s the Controls, Stupid!

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